Sophisticated mechanisms have evolved in mammals to repair the body in the event of vascular injury and so maintain hemostasis. The injured blood vessel constricts to reduce the blood flow to the area, platelets aggregate to reduce the loss of blood from the area, and fibrinogen is cleaved to produce fibrin which then polymerises and forms a clot. This clot covers the area of vascular damage, preventing blood loss. Polymerised fibrin also provides a provisional matrix which enhances the subsequent repair process. Once the blood vessel has been repaired the clot dissolves. The process leading to the formation of the clot is the coagulation cascade, and the process leading to its dissolution is the fibrinolysis cascade. Imbalances in the blood coagulation process are thought to be at the origin of a large and disparate number of disease conditions, which are linked by an unwanted build up of fibrin. The scale of fibrin build up is determined by the delicate equilibrium between the two biochemical cascades in the human body. Agents that can modulate the balance between coagulation and fibrinolysis are therefore potentially valuable in the treatment of these disease conditions.
Studies have shown that coagulation and fibrinolysis are linked through the generation of xcex1-thrombin. xcex1-Thrombin is the final product of the blood coagulation cascade and is responsible for the conversion of fibrinogen into fibrin. In addition to mediating coagulation, xcex1-thrombin also reduces the rate at which blood clots are broken down by the serine protease plasmin. The protein that mediates this antifibrinolytic effect of xcex1-thrombin is TAFI (Thrombin Activatable Fibrinolysis Inhibitor).
TAFI is a 60 kDa glycoprotein found in human plasma. It is also known as procarboxypeptidase B, carboxypeptidase B, plasma carboxypeptidase B, carboxypeptidase U and carboxypeptidase R. Following initiation of the coagulation cascade it is transformed into an activated form, TAFIa, whereupon it acts upon the fibrin matrix of the developing blood clot to prevent its dissolution. TAFI circulates in normal plasma at a concentration of about 75 nM in an inactive form. Thrombin converts the inactive zymogen to the active TAFI (TAFIa), a reaction that is augmented about 1250-fold by thrombomodulin. Once activated, TAFIa cleaves both C-terminal arginine and lysine residues from the developing fibrin clot. The removal of these dibasic amino acids from the surface of the fibrin matrix attenuates clot lysis by inhibiting the binding of the key mediators of fibrinolysis: tissue plasminogen activator (tPA) and its substrate, plasminogen, which is the precursor of plasmin. Both tPA and plasminogen contain a structural motif called a kringle domain which binds tightly to C-terminal lysine residues. The removal of these binding sites prevents the formation of a ternary complex between tPA, plasminogen and fibrin and this inhibits the conversion of plasminogen to plasmin, thus protecting the clot from rapid degradation.
In the presence of a TAFIa inhibitor, TAFIa will not be able to act upon a developing fibrin clot as described above to inhibit fibrinolysis of the clot. Thus a TAFIa inhibitor should serve to enhance fibrinolysis.
It can be seen that, in pathologies where the normal equilibrium between coagulation and fibrinolysis is disturbed in favour of coagulation, there will be a larger amount of fibrin present than normal. This makes it more likely that the subjects will develop one or more of the conditions in which thrombus build up is implicated. Such subjects can be expected to benefit from treatment with a pro-fibrinolytic agent. McKay et al. (Biochemistry 1978, 17, 401) disclose the testing of a number of compounds as competitive inhibitors of bovine carboxypeptidase B of pancreatic origin. Inhibition was measured by the inhibitor""s efficiency in protecting the active centre tyrosine and glutamic acid of bovine carboxypeptidase B from irreversible alkylation by bromoacetyl-D-arginine or bromoacetamidobutylguanidine. It is suggested that such inhibitors could act as bradykinin potentiators. Bovine enzymes of pancreatic origin are very different to those found in human plasma, so one would not expect inhibitors of one to inhibit the other. Moreover, such inhibitors are directed towards a very different utility. Accordingly this disclosure provides no teaching of TAFIa inhibitors or their utility.
Redlitz et al. (J. Clin. Invest. 1995, 96, 2534) teach the involvement of plasma carboxypeptidase B (pCPB, or TAFI) in the formation of clots. The lysis of blood clots was followed in the absence and presence of pCPB, whereupon it was found that the presence of pCPB slowed clot lysis. To confirm that pCPB was responsible two control reactions were run; one where the lysis experiment was repeated in the presence of pCPB and potato carboxypeptidase inhibitor, PCI, and a second where the lysis reaction was conducted in the presence of plasma from which pCPB was removed. In both cases lysis proceeded uninhibited.
Boffa et al. (J. Biol. Chem. 1998, 273, 2127) compare plasma and recombinant TAFI and TAFIa with respect to glycosylation, activation, thermal stability and enzymatic properties. Inhibition constants for three competitive inhibitors were determined: xcex5-aminocaproic acid xcex5-ACA), 2-guanidinoethylmercaptosuccinic acid (GEMSA) and potato carboxypeptidase inhibitor (PCI).
There are large numbers of carboxypeptidases (i.e. enzymes that cleave the C-terminal amino acid from a peptide). They may be classified as acidic, neutral or basic, depending on the type of amino acid they cleave. Basic carboxypeptidases cleave arginine, lysine and histidine. TAFIa is a member of a specific subset of the basic carboxypeptidases. In terms of the present invention, the inhibitors disclosed above by Redlitz et al. and Boffa et al. are too weak, non-specific or otherwise unsuitable to be considered as suitable TAFIa inhibitors for therapeutic application. Further, whilst the role of TAFIa in clot lysis is explained, there is no suggestion that TAFIa inhibitors can be used to treat disease.
U.S. Pat. No. 5,993,815 teaches the use of a peptide that binds to the TAFI zymogen, thereby inhibiting its activation, to treat those disorders where a C-terminal lysine or arginine is cleaved from an intact peptide. Suitable disorders are arthritis, sepsis, thrombosis, strokes, deep vein thrombosis and myocardial infarctions. The peptide used is an antibody or a functionally active fragment. The peptide should be used in an amount to promote fibrinolysis in vivo.
WO00/66550 and WO00/66557 disclose broad classes of compounds useful as inhibitors of carboxypeptidase U. Inhibitors of carboxypeptidase U are postulated to facilitate fibrinolysis and thus the compounds are taught as useful in the treatment of thrombotic conditions. There is no data to support this assertion, though details of a suitable assay are given.
WO00/66152 discloses formulations containing a carboxypeptidase U inhibitor and a thrombin inhibitor. Suitable carboxypeptidase U inhibitors are those of WO00/66550. The formulations are taught as primarily useful in treating thrombotic conditions.
WO01/19836 discloses a series of phosphonate esters and analogues thereof as carboxypeptidase B inhibitors that are suitable for the treatment or prevention of thrombotic diseases.
WO02/14285 discloses a series of xcex1-imidazolylmethyl-xcfx89-aminocarboxylic acids and Nxcex1-(xcfx89-aminoalkyl)-histidine derivatives that are inhibitors of TAFIa. The compounds are considered to be potentially useful in the treatment of a number of conditions.
The present invention discloses a further class of TAFIa inhibitors.
In a first aspect, the present invention provides compounds according to general formula (I) 
wherein:
n is 0, 1, 2 or 3;
R1 is selected from
(a) an optionally substituted straight chain or branched chain C1-6 alkyl group,
(b) an optionally substituted straight chain or branched chain C2-6 alkenyl group,
(c) an optionally substituted straight chain or branched chain C2-6 alkynyl group,
(d) Aryl,
(e) Aromatic heterocycle,
(f) Heterocycle, and
(g) hydrogen;
where the optional substituents in groups (a), (b) and (c) above are selected from: C3-7 cycloalkyl, Aryl, Aromatic heterocycle, Heterocycle, OR10, NR10R11, S(O)pR10, OC(O)R11, CO2R10, CONR10R11, SO2NR10R11, halo and NHSO2R10, and where p is 0, 1 or 2;
R2, R3, R4, R6, R7 and R9 are each independently selected from hydrogen and straight chain or branched chain C1-6 alkyl optionally substituted by OR10 or halo;
R5 and R8 are each independently selected from hydrogen and straight chain or branched chain C1-6 alkyl optionally substituted by OR10 or halo, or together are a C2-6 alkylene chain;
R10 and R11 are each independently selected from hydrogen and straight chain or branched chain C1-6alkyl;
Aryl is a 6-14 membered aromatic monocyclic or fused polycyclic carbocyclic group optionally substituted with one or more groups selected from R12, halo, OR13, NR13R14, NR13CO2R12, CO2R13, NR13SO2R12, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, SO2NR13R14, C(O)NR13R14, C3-7 cycloakyl, O(C3-7 cycloalkyl), R15 and OR15, where R12 is straight chain or branched chain C1-6 alkyl, R13 and R14 are each independently selected from hydrogen and straight chain or branched chain C1-6 alkyl, and R15 is phenyl optionally substituted by R12, OR13, halo or haloalkyl;
Aromatic heterocycle is a 5 to 7 membered aromatic ring containing from 1 to 3 heteroatoms, each independently selected from O, S and N, said ring being optionally substituted with one or more groups selected from OR13, NR13R14, CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14 and C(O)NR13R14; and
Heterocycle is a 3 to 8 membered ring containing from 1 to 3 heteroatoms, each independently selected from O, S and N, said ring being saturated or partially saturated, said ring further being optionally substituted with one or more groups selected from OR13, NR13R14, CO2R13, NR13CO2R14, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14 and C(O)NR13R14,
or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of said compound or said tautomer.
As used herein:
i) Halo includes fluoro, chloro, bromo and iodo groups.
ii) Haloalkyl includes monohaloalkyl, polyhaloalkyl and perhaloalkyl, such as 2-bromoethyl, 2,2,2-trifluoroethyl, chlorodifluoromethyl and trichloromethyl.
iii) Unless otherwise indicated, alkyl includes straight chain and branched chain alkyl.
It will be understood that, in the compounds according to general formula (I), the R1 group and C(R2)(R3)(amino acid) group may be attached at any atom of the imidazole ring that is available to form a covalent bond, and that it is not intended that the general formula should be interpreted as limiting the R1 group to the C2- and N3-positions, nor the C(R2)(R3)(amino acid) group to the C4- and C5-positions. It will further be understood that the two groups cannot both be attached to the same atom of the imidazole ring, and that only one of the nitrogen atoms (by convention designated N1) of the imidazole ring is available to form a covalent bond. Thus the possible substitution patterns are 1,2-; 1,4-; 1,5-; 2,4- and 2,5-. When the imidazole is 2,4- or 2,5-substituted then there is a hydrogen atom attached at the N1-position.
Certain compounds according to formula (I) may exist in more than one tautomeric form. If the imidazole of general formula (I) is substituted at the 2- and 4-positions the 2,4-disubstituted imidazole can tautomerise to form the corresponding 2,5-disubstituted imidazole. Furthermore, where a compound includes an Aromatic heterocyle that is substituted with a hydroxyl group it may exist as the xe2x80x98ketoxe2x80x99 tautomer. The tautomeric relationship between 2-hydroxypyridine and 2-pyridone is a well known example of this phenomenon. All such tautomers of compounds of formula (I), including mixtures thereof, are included in the scope of the present invention.
The compounds of formula (I) contain one or more asymmetric carbon atoms (chiral centers) and can therefore exist in two or more optical stereoisomeric forms such as enantiomers, diastereomers and epimers. Where the compounds of formula (I) contain a carbon-carbon double bond, cis (Z)/trans (E) stereoisomerism may also occur. All such individual stereoisomers of the compounds of formula (I) and mixtures thereof, including racemates, are included in the scope of the present invention.
Individual stereoisomers may be separated from mixtures by conventional techniques such as, for example, by fractional crystallization or by chromatography of the mixture of compounds or of a suitable salt or derivative thereof. In particular, individual enantiomers of the compounds of formula (I) may be prepared by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate. The individual enantiomers may also be obtained from a corresponding optically pure intermediate prepared by such a resolution method. These general principles are discussed in more detail by J. Jacques and A. Collet (xe2x80x9cEnantiomers, Racemates and Resolutionsxe2x80x9d, Wiley, N.Y., 1981) and by W. Liu (xe2x80x9cHandbook of Chiral Chemicalsxe2x80x9d, D. Ager (ed.), M. Dekker, N.Y., 1999; chapter 8).
It will be appreciated that the compounds of formula (I) have both acidic and basic functional groups. Therefore, in addition to the uncharged form depicted in the general formula, they may exist as internal salts (zwitterions). Furthermore, they may form pharmaceutically acceptable salts with acids and bases. Such zwitterions and salts are included within the scope of the invention.
A pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. Salts may also be prepared by ion exchange, such as by equilibrating a solution of a compound of formula (I) with an appropriate ion exchange resin. Ion exchange may also be used to convert one salt form of a compound of formula (I), such as a salt with an acid or base that is not pharmaceutically acceptable, to another salt form. These methods are generally well known in the art. Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts. For a review of pharmaceutically acceptable salts see Berge et al. (J. Pharm. Sci., 1977, 66, 1).
The compounds of formula (I) may form pharmaceutically acceptable solvates (including hydrates). These solvates are also included in the scope of the present invention.
The compounds of formula (I) may exist in one or more crystalline forms. These polymorphs, including mixtures thereof are also included within the scope of the present invention.
The scope of the present invention further includes prodrugs of compounds of formula (I), i.e. pharmaceutically acceptable derivatives of the compounds in which one or more of the functional groups explicitly recited above have been modified such that they are converted to the parent compounds in vivo. Suitable prodrugs are discussed in Drugs of Today 1983, 19, 499-538 and Annual Reports in Medicinal Chemistry 1975, 10, 306-326.
The absolute stereochemistry of the compounds of formula (I) may be as depicted in formula (IA) or formula (IB) below. By convention the absolute stereochemistry at the chiral center of (IA) is designated as xe2x80x98Sxe2x80x99 and that of (IB) is xe2x80x98Rxe2x80x99. The compounds of formula (IA) are particularly preferred. 
Preferred compounds of formula (I) include those where the imidazole is substituted at the C2 or C4 positions by the C(R2)(R3)(amino acid) group to give compounds of formulae (IC) and (ID) respectively. Particularly preferred are those compounds of formula (I) where R1 is attached at the C4 position of the imidazole moiety and the C(R2)(R3)(amino acid) group is attached at the C2 position so as to give the 2,4-disubstituted imidazole of formula (IC1) or where R1 is attached at the N1 position of the imidazole moiety and the C(R2)(R3)(amino acid) group is attached at the C4 position so as to give the 1,4-disubstituted imidazole of formula (ID1). Most preferred are those compounds of formula (I) where R1 is attached at the N1 position of the imidazole moiety and the C(R2)(R3)(amino acid) group is attached at the C4 position so as to give the 1,4-disubstituted imidazole of formula (ID1). 
Preferably n is 0 or 1. More preferably n is 0.
Preferably R1 is hydrogen, Aryl, or a C1-6 alkyl or C2-6 alkenyl group optionally substituted by one or more groups selected from C3-7 cycloalkyl, Aryl, Aromatic heterocycle, Heterocycle, OR10, NR10R11, S(O)pR10, OC(O)R11, CO2R10, CONR10R11, SO2NR10R11, halo and NHSO2R10. More preferably R1 is hydrogen, Aryl, C2-6 alkenyl or a C1-6 alkyl group optionally substituted by one or more groups selected from C3-7 cycloalkyl, Aryl, Aromatic heterocycle, OR10, CO2R10, halo and NHSO2R10. Yet more preferably R1 is hydrogen, Aryl or a C1-6 alkyl group optionally substituted by a group selected from C3-7 cycloalkyl, Aryl, Aromatic heterocycle, OR10, CO2R10 and NHSO2R10. Yet more preferably R1 is hydrogen, Aryl or a C1-6 alkyl group optionally substituted by a group selected from cyclohexyl and Aryl. Yet more preferably R1 is hydrogen or C1-3 alkyl. Most preferably R1 is hydrogen.
Preferably R2 and R3 are each independently selected from hydrogen and C1-6 alkyl More preferably R2 and R3 are hydrogen.
Preferably R4 is hydrogen or C1-6 alkyl. More preferably R4 is hydrogen.
Preferably R6, R7 and R9 are each independently selected from hydrogen and C1-6 alkyl. More preferably R6, R7 and R9 are each independently selected from hydrogen and C1-3 alkyl. Yet more preferably R6, R7 and R9 are each independently selected from hydrogen and methyl. Most preferably R6, R7 and R9 are all hydrogen.
When R5 and R8 do not constitute a C2-6 alkylene link then R5 is preferably hydrogen or C1-6 alkyl, more preferably hydrogen or C1-3 alkyl, yet more preferably hydrogen or methyl, and most preferably methyl, and R8 is preferably hydrogen or C1-6 alkyl, more preferably hydrogen or C1-3 alkyl, yet more preferably hydrogen or methyl, and most preferably hydrogen.
When R5 and R8 constitute a C2-6 alkylene link then the link is preferably a C2-3 alkylene link and more preferably it is a C2 alkylene link.
Preferably R10 and R11 are each independently selected from hydrogen and C1-3 alkyl. More preferably R10 and R11 are each independently selected from hydrogen and methyl.
Aryl includes optionally substituted phenyl, naphthyl, anthracenyl and phenanthrenyl. Preferably Aryl is phenyl or naphthyl optionally substituted by 1-3 groups selected from R12, halo, OR13, NR13R14, NR13CO2R12, CO2R13, NR13SO2R12, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, SO2NR13R14, C(O)NR13R14, C3-7 cycloakyl, O(C3-7 cycloalkyl), R15 and OR15. More preferably Aryl is phenyl optionally substituted by C1-6 alkyl, halo, O(C1-6 alkyl), CF3, C3-7 cycloakyl, O(C3-7 cycloalkyl), R15 or OR15 and R15 is phenyl optionally substituted by C1-6 alkyl, halo, O(C1-6 alkyl) or CF3. Yet more preferably Aryl is phenyl optionally substituted by C1-6 alkyl, CF3, cyclohexyl, O(cyclohexyl), R15 or OR15 and R15 is phenyl optionally substituted by C1-6 alkyl, Cl, F, O(C1-6 alkyl) or CF3. Most preferably Aryl is phenyl.
Preferably Aromatic heterocycle is a 5 or 6 membered aromatic ring containing 1 or 2 heteroatoms each independently selected from O, S and N, including optionally substituted furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, optionally substituted by 1-3 groups selected from OR13, NR13R14, CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14, C(O)NR13R14. More preferably Aromatic heterocycle is a 5 or 6 membered aromatic ring containing from 1 to 3 heteroatoms, each independently selected from O, S and N, optionally substituted by 1-3 groups selected from OR13, NR13R14, CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14, C(O)NR13R14. Most preferably Aromatic heterocycle is an unsubstituted 5 or 6 membered aromatic ring containing 1 or 2 heteroatoms, each independently selected from O, S and N.
Preferably, Heterocycle is a 3 to 8 membered ring containing 1 or 2 heteroatoms, each independently selected from O, S and N, said ring being saturated or partially saturated, optionally substituted by 1 to 3 groups selected from OR13, NR13R14, CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14, C(O)NR13R14. More preferably, Heterocycle is a 5 or 6 membered ring containing 1 or 2 heteroatoms, each independently selected from O, S and N, said ring being saturated or partially saturated, optionally substituted by 1 to 3 groups selected from OR13, NR13R14, CO2R13, NR13CO2R12, R12, halo, CN, haloalkyl, O(haloalkyl), SR13, S(O)R12, SO2R12, OC(O)R13, NR13SO2R12, SO2NR13R14, C(O)NR13R14. Most preferably, Heterocycle is an unsubstituted 5 or 6 membered ring containing 1 or 2 heteroatoms, each independently selected from O, S and N, said ring being saturated or partially saturated, including oxiranyl, azetidinyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, morpholinyl, piperidinyl and piperazinyl.
Preferred compounds of the present invention are:
(2S)-(xe2x88x92)-2-(2-aminoethoxy)-3-(1-phenyl-1H-imidazol-4-yl)propanoic acid (Example 6);
(2S)-2-{[(1R)-2-amino-1-methylethyl]oxy}-3-[1-(2-cyclohexylethyl)-1H-imidazol-4-yl]propanoic acid (Example 15);
(2S)-2-{[(1R)-2-amino-1-methylethyl]oxy}-3-(1-phenyl-1H-imidazol-4-yl)propanoic acid (Example 17);
(2S)-2-{[(2S)-2-aminopropyl]oxy}-3-[1-(2-cyclohexylethyl)-1H-imidazol-4-yl]propanoic acid (Example 34);
(2S)-2-(2-aminoethoxy)-3-(1H-imidazol-4-yl)propanoic acid (Example 50);
(2S)-2-{[(1R)-2-amino-1-methylethyl]oxy}-3-(1H-imidazol-4-yl)propanoic acid (Example 51); and
(2S)-2-{[(1R)-2-amino-1-methylethyl]oxy}-3-[1-(2-pyridinyl)-1H-imidazol-4yl]propanoic acid (Example 52).
Particularly preferred is (2S)-2-{[(1R)-2-amino-1-methylethyl]oxy}-3-(1H-imidazol-4-yl)propanoic acid (Example 51).
The compounds of formula (I) are inhibitors of TAFIa. Inhibition of TAFIa can be demonstrated using an assay based on the method of Boffa et al. (J. Biol. Chem. 1998, 273, 2127) as further described below. The activity of the compounds is characterized by a calculated Ki value. Generally the compounds of the present invention have a Ki value of 10 xcexcM or less. Better compounds have a Ki value of 1 xcexcM or less, or even 100 nM or less. The most potent compounds have a Ki value of 25 nM or less.
The compounds of formula (I) are selective for TAFIa over other carboxypeptidases, and particularly carboxypeptidase N (CPN). Unwanted inhibition of CPN is considered to be the most likely cause of undesirable side effects in clinical use. Selectivity can be expressed as the ratio of the Ki for TAFIa to the Ki for CPN. Generally the compounds of the present invention have a selectivity ratio of at least 5. Better compounds have a selectivity ratio of at least 10. The most selective compounds have a selectivity ratio of at least 50.
The compounds of formula (I) may be prepared according to the general methods which are described below and in the Examples and Preparations section. These methods provide a further aspect of the present invention. Nevertheless, the skilled man will appreciate that the compounds of the invention could be made by methods other than those herein described, by adaptation of the methods herein described and/or adaptation of a plethora of methods known in the art. It is to be understood that the synthetic transformation methods specifically mentioned herein may be carried out in various different sequences in order that the desired substances can be efficiently assembled. The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for the synthesis of a given target substance.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during the synthesis of a substance of the invention. This may be achieved by conventional techniques, for example as described by T. W. Greene and P. G. M. Wuts (xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 3RD edition, Wiley-Interscience, N.Y., 1999).
Compounds of formula (I) may be prepared from the corresponding esters of formula (II) (wherein P1 is a lower alkyl group, a benzyl group or any other carboxyl protecting group). 
P1 is preferably a lower alkyl group such as methyl or ethyl, in which case suitable conditions for this step include treatment with NaOH in dioxan for 1-3 days.
Compounds of formula (II) may be prepared from the corresponding protected amines of formula (III) (wherein p2 is a tert-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonyl group, or any other amine protecting group). Where R9 is H then the preparation involves only a deprotection step. Where R9 is other than H then a further step is necessary to introduce R9, such as a reductive amination reaction. 
Alternatively, compounds of formula (III) may be converted to the corresponding acids (IV) prior to deprotecting the amine to give the compounds of formula (I). 
Compounds of formula (III) may be prepared from imidazoleacetic acid derivatives of formula (V), wherein X is a leaving group such as a chlorine, bromine or iodine atom, or a methanesulphonate or trifluoromethanesulphonate group, by reaction with a alcohol of formula (VI). 
Compounds of formula (V) may be prepared from the corresponding hydroxyacid derivatives of formula (VII) or, where X is Br, by direct halogenation of the esters of formula (VIII). 
Compounds of formula (VI), (VII) and (VIII) are known or may be prepared by methods analogous to those used for the preparation of such known compounds.
Compounds of formula (III) may alternatively be prepared from xcex1-hydroxyimidazole-acetic acid derivatives of formula (VII) by reaction with a compound of formula (IX) wherein Y is a leaving group such as a chlorine, bromine or iodine atom, or a methanesulphonate or trifluoromethanesulphonate group. 
Compounds of formula (II) where neither of R8 and R9 are hydrogen may also be prepared from compounds of formula (X). When R3 is hydrogen the transformation may be accomplished by hydrogenation in the presence of a suitable catalyst. When R3 is other than hydrogen the transformation may be accomplished using a reagent such as R3-M, where M is a metal such as lithium or magnesium, in the presence of a copper(I) salt. 
Compounds of formula (X) may be prepared from compounds of formula (XI) by dehydration. The transformation may be accomplished using, for example, methanesulfonyl chloride and a tertiary amine. 
Compounds of formula (XI) may be prepared by an aldol-type reaction between alkoxy-esters of formula (XII) and aldehydes or ketones of formula (XIII) in the presence of a strong base, such as lithium diisopropylamide. 
Compounds of formula (XIII) are generally known, or may be prepared by methods analogous to published methods. Compounds of formula (XII) may be prepared by reacting the corresponding amino-alcohols R8R9NC(R6)(R7)(CH2)nC(R4)(R5)OH with a bromoacetate BrCH2CO2P1 in the presence of a base such as sodium hydride.
Compounds of formula (I) wherein R9 is hydrogen may alternatively be prepared by the hydrolysis of lactams of formula (XIV). 
Compounds of formula (XIV) may be prepared from the corresponding unsaturated compounds of formula (XV). When R3 is hydrogen the transformation may be accomplished by hydrogenation in the presence of a suitable catalyst. When R3 is other than hydrogen the transformation may be accomplished using a reagent such as R3xe2x80x94M, where M is a metal such as lithium or magnesium, in the presence of a copper(I) salt. 
Compounds of formula (XV) may be prepared by dehydration of alcohols of formula (XVI). 
Compounds of formula (XVI) may be prepared by reacting an aldehyde or ketone of formula (XIII) with a lactam of formula (XVII) in the presence of a strong base, such as lithium diisopropylamide. 
Compounds of formula (XVII) may be prepared from aminoalcohols of formula (XVIII) by reaction with chloroacetyl chloride. Compounds of formula (XVIII) are generally known, or may be prepared by adaptation of generally known methods. 
When R8 is H, the foregoing method can be problematic, particularly at the step involving the reaction of compounds of formula (XIII) and (XVII). It is generally convenient in this case to use a protected aminoalcohol of formula (XVIIIa), where P3 is a nitrogen protecting group. A particularly useful embodiment of P3 is the 4-methoxybenzyl group. This may be removed following the elaboration of intermediate (XIVa) by treatment with ceric ammonium nitrate. 
When R1 is H it may be necessary or convenient to protect the imidazole as its trityl derivative. Accordingly, when R1 is H, compounds of formula (XIX), (XX) or (XXI) may be elaborated by the foregoing methods to provide compounds of formula (XXII) which, upon deprotection, give compounds of formula (III). 
This route may also be useful for the preparation of certain compounds according to formula (I) wherein R1 is attached at the N1 position of the imidazole ring. Compounds of formula (III) wherein R1 is H may be alkylated or arylated to give compounds of formula (III) wherein R1 is other than H and is attached at the N1 position. 
When R1 is an alkyl, alkenyl or alkynyl group it may be introduced in an alkylation reaction. Suitable conditions for this step include treatment with 1.1 eq of cesium carbonate and 1.1 eq of an alkylating agent in N,N-dimethylformamide, or with sodium hydride and 1.1 eq of an alkylating agent in THF. Suitable alkylating reagents include R1xe2x80x94Cl, R1xe2x80x94Br, R1xe2x80x94I, R1xe2x80x94OSO2CH3 and R1xe2x80x94OSO2CF3. When R1 is Aryl or Aromatic heterocycle it may be introduced in an arylation reaction. Suitable conditions for this step include treatment with 2 eq of Aryl-B(OH)2 or Aromatic heterocycle-B(OH)2 in the presence of 1.5 eq of copper acetate, 2 eq of pyridine, air and 4 xc3x85 molecular sieves.
For the compounds of formula (I) wherein the imidazole is 2,4- or 2,5-disubstituted, it may also be convenient or necessary to use a protecting group at the N1 position.
The compounds of formula (I) are useful as therapeutic agents. The compounds will generally be formulated so as to be amenable to administration to the subject by the chosen route. In a further aspect, therefore, the present invention provides for a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compounds of formula (I) can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions. These formulations may contain flavouring or colouring agents, and may be adapted for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose and derivatives thereof, milk sugar and high molecular weight polyethylene glycols.
For solutions, suspensions and elixirs, the compounds of formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents, and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
The compounds of formula (I) may also be administered in the form of a solution- or suspension-filled soft or hard gelatin capsule. Such capsules are generally made of gelatin, glycerin, water and sorbitol. Hard capsules are distinguished from soft capsules by containing less water and thus having a correspondingly stronger shell. Additional excipients suitable for use in such capsules include propylene glycol, ethanol, water, glycerol and edible oils.
The compounds of formula (I) can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously. Such administration may be as a single bolus injection or as a short- or long-duration infusion. For such parenteral administration the compounds are preferably formulated as a sterile solution in water or another suitable solvent or mixture of solvents. The solution may contain other substances such as: salts, particularly sodium chloride, and sugars, particularly glucose or mannitol, to make the solution isotonic with blood; buffering agents such as acetic, citric and phosphoric acids and their sodium salts, such that the pH of the solution is preferably between 3 and 9; and preservatives. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
The compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A(trademark)) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA(trademark)), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch.
Alternatively, the compounds of formula (I) can be administered by the vaginal or rectal routes in the form of a suppository or pessary, or The compounds of formula (I) may also be administered dermally or transdermally, for example, by the use of a skin patch.
Alternatively, the compounds of formula (I) can be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. Suitable ointments may contain the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Suitable lotions or creams may contain the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Alternatively, the compounds of formula (I) may be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
The compounds of formula (I) may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO91/11172, WO94/02518 and WO98/55148.
Because the compounds of formula (I) are inhibitors of TAFIa they are useful as therapeutic agents in pathologies in which inhibition of TAFIa is beneficial. In a further aspect, therefore, the present invention provides for a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or prodrug thereof for use as a medicament. In particular, the present invention provides for the use of a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for the treatment or prevention of a condition selected from thrombotic conditions, atherosclerosis, adhesions, dermal scarring, cancer, fibrotic conditions, inflammatory diseases and those conditions which benefit from maintaining or enhancing bradykinin levels in the body. The utility of TAFIa inhibitors for the treatment of thrombotic conditions derives from their potential to promote fibrinolysis while not interfering with coagulation. In most clinically relevant situations thrombus formation is sub-acute, i.e. the thrombus forms slowly. Conventional anti-thrombotic agents block the coagulation pathway and so prevent thrombus growth, but as an unavoidable consequence they also block the clotting response to vascular damage, which results in an increased incidence of hemorrhaging. By promoting fibrinolysis, TAFIa inhibitors accelerate the dissolution of the developing thrombus without interfering with the clotting response. Accordingly, one preferred embodiment of the present invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof in the preparation of a medicament for the treatment of a thrombotic condition selected from myocardial infarction, deep vein thrombosis, stroke, young stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, peripheral vascular disease, angina and other forms of acute coronary syndromes, disseminated intravascular coagulation, sepsis, pulmonary embolism, embolic events secondary to cardiac arrhythmias and the prevention of cardiovascular events following surgical revascularisation or intervention, or for improving the outcome of organ transplantation by reducing blood clotting and so preserving organ function. Cardiovascular events following intervention surgery include conditions such as restenosis or reocclusion following interventions such as percutaneous transluminal coronary angioplasty, grafting, stent in-placement, coronary bypass surgery or any other forms of surgical revascularisation or intervention. Disseminated intravascular coagulation includes all conditions resulting from intravascular activation of the coagulation process. This might occur acutely through the release of procoagulant substances (eg. obstetric emergencies, snakebite, crush injury malignancy), by abnormal contact of the blood (eg. infections, burns, extracorporeal circulation, grafts) or though generation of procoagulants in the blood (transfusion reactions, leukemia); or chronically, (eg. toxemia, malignant hypertension, severe liver cirrhosis). Deep vein thrombosis also encompasses what is known as xe2x80x98economy class syndromexe2x80x99, where clots form in subjects forced to endure cramped conditions for a period of time, such as those sitting in the economy class seats of an aeroplane.
A role for thrombus formation in the pathophysiology of atherosclerosis has recently been highlighted by several independent groups. Non-occlusive thrombi not only restrict blood flow leading to myocardial ischemia and angina pectoris but also, due to incomplete endogenous lysis, may be incorporated into the arterial wall as solidified plaque material enhancing the atherosclerotic process. Long-term administration of a TAFIa inhibitor promotes the lysis of developing thrombi and therefore provides a safe and efficacious treatment which alleviates the symptoms of angina pectoris while impairing the progression of the underlying disease. Conventional treatment of myocardial ischaemia in clinically stable coronary artery disease is predominately designed to reduce cardiac workload and enhance blood flow. Such approaches clearly reduce myocardial ischaemia thus increasing quality of life. However, these strategies have little effect on the pathogenesis of coronary atherosclerosis which is a chronic process of continuous remodeling of the vascular tree in response to varying degrees of vascular injury. Accordingly, another preferred embodiment of the present invention provides for the use of compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof in the preparation of a medicament for the treatment or prevention of atherosclerosis, including atherosclerosis as a consequence of peripheral vascular disease, insulin resistance and Syndrome X, and further including myocardial ischaemia and angina pectoris resulting from atherosclerosis. Atherosclerosis is taken to include both primary and secondary coronary artery disease, in which atherosclerosis restricts the blood supply to the heart. Primary prevention of coronary artery disease means preventing the onset of ischemic complications such as myocardial infarction in patients with no history of coronary artery disease but who have one or more risk factors. Secondary prevention of coronary artery disease means preventing ischemic complications in patients with established coronary artery disease, such as patients who have had a previous myocardial infarction. Syndrome X is a term often used to group together a number of interrelated diseases. The first stage of syndrome X consists of insulin resistance, abnormal cholesterol and triglyceride levels, obesity and hypertension. Any one of these conditions may be used to diagnose the start of Syndrome X. The disease may then progress with one condition leading to the development of another in the group. For example insulin resistance is associated with high lipid levels, hypertension and obesity. The disease then cascades, with the development of each additional condition increasing the risk of developing more serious diseases. This can progress to the development of diabetes, kidney disease and heart disease. These diseases may lead to stroke, myocardial infarction and organ failure. Atherosclerosis is common in patients with Syndrome X.
TAFIa inhibitors are also effective in preventing the formation of adhesions in the body. Most surgical procedures and physical traumas result in bleeding into the cavities between tissues. The blood which collects at these sites then clots forming fibrin-rich thrombi. These thrombi bridge the gaps between adjacent tissues and act as foci for the accumulation of inflammatory cells and fibroblasts. Invading fibroblasts lay down a collagen-rich extracellular matrix which strengthens the adhesion of the tissues producing a firm bond which may then restrict movement. Adhesions have been characterised according to their location and may result following any surgery, e.g. abdominal, orthopaedic, neurological, cardiovascular and ocular surgery. This inappropriate adhesion of tissues post-surgery or trauma is a major issue which can lead to various outcomes, e.g. xe2x80x9caches and painsxe2x80x9d, xe2x80x9ctwingesxe2x80x9d, local inflammation, restriction in mobility, pain, intestinal obstruction and sometimes, in the most severe cases, death. In the case of gynaecological surgery, infertility may result. Additionally clots forming fibrin-rich thrombi are implicated in dermal scarring and restenosis. Without being bound by any theory, it is believed that adhesion formation may be enhanced when a deficiency in fibrinolysis results in enhanced and maintained clot formation. Treatment with a TAFIa inhibitor around and/or after surgical intervention may enhance fibrinolysis of the fibrin-rich thrombi and hence inhibit thrombus formation, accretion and stabilization, thereby inhibiting adhesion formation. A TAFIa inhibitor given either locally as a topical application or systemically may be seen to be of benefit in a range of surgical procedures. In addition, administration of a TAFIa inhibitor may be used to treat adhesions resulting from other forms of non-surgical physical trauma where this has caused internal bleeding. Examples of such trauma might include sporting injuries or anything else resulting in a tear, cut, bruise or induration of the body. Accordingly, another preferred embodiment of the present invention provides for the use of compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof in the preparation of a medicament for the treatment or prevention of a medicament for the treatment or prevention of adhesions or dermal scarring.
TAFIa inhibitors are also effective in inhibiting tumour maturation, progression and metastasis. Without being bound by any theory, it is believed that the hemostatic system is involved at several levels of cancer pathology, including neovascularisation, shedding of cells from the primary tumour, invasion of the blood supply, adherence to the vessel wall and growth at the metastatic site. It is thought that the efficacy of TAFIa inhibitors stems from an ability to reduce fibrin deposition around solid tumours and thereby inhibit the above processes. Accordingly, another preferred embodiment of the present invention provides for the use of compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof in the preparation of a medicament for the treatment or prevention of cancer.
TAFIa inhibitors are efficacious in treatment of any condition in which fibrosis is a contributing factor. Suitable fibrotic conditions include cystic fibrosis, pulmonary fibrotic diseases such as chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), fibromuscular dysplasia and fibrotic lung disease, and fibrin deposition in the eye during opthalmic surgery. Accordingly, another preferred embodiment of the present invention provides for the use of compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof in the preparation of a medicament for the treatment or prevention of fibrotic disease, and in particular for the treatment or prevention of a fibrotic condition selected from cystic fibrosis, pulmonary fibrotic diseases, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), fibromuscular dysplasia, fibrotic lung disease and fibrin deposition in the eye during opthalmic surgery.
TAFIa inhibitors are efficacious in the treatment of inflammation, inflammatory diseases such as asthma, arthritis, endometriosis, inflammatory bowel diseases, psoriasis and atopic dermatitis and neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease. Accordingly, another preferred embodiment of the present invention provides for the use of compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof in the preparation of a medicament for the treatment or prevention of inflammation, inflammatory diseases such as asthma, arthritis, endometriosis, inflammatory bowel diseases, psoriasis and atopic dermatitis and neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease.
TAFIa binds to and breaks down bradykinin (Tan et al., Biochemistry 1995, 34, 5811). There are many conditions which are known to benefit from maintaining or enhancing levels of bradykinin such as hypertension, angina, heart failure, pulmonary hypertension, renal failure and organ failure. Accordingly, another preferred embodiment of the present invention provides for the use of compounds of formula (I) and pharmaceutically acceptable salts, solvates and prodrugs thereof in the preparation of a medicament for the treatment or prevention of conditions which benefit from maintaining or enhancing levels of bradykinin.
In a further aspect, the present invention provides a method of treating or preventing thrombotic conditions, atherosclerosis, adhesions, dermal scarring, cancer, fibrotic conditions, inflammatory diseases and those conditions which benefit from maintaining or enhancing bradykinin levels in the body which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof to a patient in need of such treatment.
One preferred embodiment of the present invention provides for a method of treating or preventing thrombosis, particularly myocardial infarction, deep vein thrombosis, stroke, young stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, peripheral vascular disease, angina and other forms of acute coronary syndromes, disseminated intravascular coagulation, sepsis, pulmonary embolism, embolic events secondary to cardiac arrhythmias and preventing cardiovascular events following intervention surgery which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof to a patient in need of such treatment. Subjects with thrombotic conditions who are suitable for treatment by the present invention include those having conditions associated with hypercoagulability, such as factor V mutation, antithrombin III deficiency, heparin cofactor II deficiency, protein C deficiency, protein S deficiency and polycythemia vera, and those exhibiting homocystinaemia or homocystinuria.
Another preferred embodiment of the present invention provides for a method of treating or preventing atherosclerosis which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof to a patient in need of such treatment.
Another preferred embodiment of the present invention provides for a method of treating or preventing adhesions or dermal scarring which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof to a patient in need of such treatment.
Another preferred embodiment of the present invention provides for a method of treating or preventing cancer which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof to a patient in need of such treatment.
Another preferred embodiment of the present invention provides for a method of treating or preventing a fibrotic condition such as cystic fibrosis, pulmonary fibrotic diseases, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), fibromuscular dysplasia, fibrotic lung disease and fibrin deposition in the eye during ophthalmic surgery which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof to a patient in need of such treatment.
Another preferred embodiment of the present invention provides for a method of treating or preventing an inflammatory disease such as asthma, arthritis, endometriosis, inflammatory bowel diseases, psoriasis or atopic dermatitis or a neurodegenerative disease such as Alzheimer""s disease or Parkinson""s disease which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof to a patient in need of such treatment.
Another preferred embodiment of the present invention provides for a method of treating or preventing conditions which benefit from maintaining or enhancing levels of bradykinin which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof to a patient in need of such treatment.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The amount of compound administered and the frequency of administration will be determined by the attending physician taking into account the characteristics of the patient, such as age, weight and state of health, and the degree of inhibition of TAFIa desired. The total daily dose for a typical 70 kg adult will generally be between 1 mg and 5 g, preferably between 10 mg and 1 g, more preferably between 50 mg and 750 mg. The total dose may be given as a single or divided dose.
The compounds of the present invention may be used alone or in combination with other therapeutic agents. When used in combination with another therapeutic agent the administration of the two agents may be simultaneous or sequential. Simultaneous administration includes the administration of a single dosage form that comprises both agents and the administration of the two agents in separate dosage forms at substantially the same time. Sequential administration includes the administration of the two agents according to different schedules provided that there is an overlap in the periods during which the treatment is provided. Suitable agents with which the compounds of formula (I) can be co-administered include antithrombotics, including antiplatelet agents, anticoagulants and profibrinolytics. Suitable antithrombotics include: aspirin, Plavix(trademark), ticlopidine, warfarin (Coumadin(trademark)), unfractionated heparin, hirudin (Lepirudin(trademark)), streptokinase, urokinase, recombinant tissue plasminogen activator (tPA), dipyridamole, Reopro(trademark), Aggrastat(trademark), and Integrilin(trademark). The compounds of formula (I) can also be administered together with antihypertensive agents and with agents to treat dyslipidaemia such as statins eg Lipitor(trademark). Further suitable drug classes for co-administration include Factor X inhibitors and antiarrhythmics such as amiodarone or digoxin. Accordingly, in a further aspect, the present invention provides for the use of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof in combination with an antithrombotic agent for the preparation of a medicament for the treatment of thrombosis. In a preferred embodiment the antithrombotic is an profibrinolytic. In a more preferred embodiment the antithrombotic is recombinant tissue plasminogen activator (tPA).
In a further aspect, the present invention provides for a method of treating or preventing thrombosis, which comprises administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof in combination with an antithrombotic to a patient in need of such treatment. In a preferred embodiment the antithrombotic is a profibrinolytic. In a more preferred embodiment the antithrombotic is recombinant tissue plasminogen activator (tPA).
In a further aspect, the present invention provides for a kit comprising:
a) a composition comprising a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof as disclosed herein and a pharmaceutically acceptable diluent or carrier;
b) a composition comprising an antithrombotic and a pharmaceutically acceptable diluent or carrier; and
c) a container
The components of this kit may be administered separately, simultaneously or sequentially.
The present invention also provides for the use a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof as a coating on intravascular devices such as indwelling catheters for dialysis, replacement heart valves or arterial stents; and as a coating on extra-corporeal blood circulation devices such as heart, lung and kidney dialysis machines, to prevent thrombosis, particularly myocardial infarction, deep vein thrombosis, stroke, young stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, peripheral vascular disease, angina and other forms of acute coronary syndromes, disseminated intravascular coagulation, sepsis, pulmonary embolism, embolic events secondary to cardiac arrhythmias and the prevention of cardiovascular events such as restenosis following intervention surgery such as percutaneous transluminal coronary angioplasty, grafting, stent in-placement, coronary bypass surgery or any other forms of surgical revascularisation or intervention.
The invention provides for intravascular devices, of which the intravascular portion is coated with a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof; and extra corporeal blood circulation devices such as heart, lung and kidney dialysis machines, where the portion coming into contact with the subjects blood is coated with a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt, solvate or prodrug thereof.
The compounds of the present invention are TAFIa inhibitors, whose utility is based upon preventing the reaction between a developing thrombus and TAFIa. It has been found that the compounds of the present invention are also capable of binding to the unactivated TAFI molecule, at the site implicated in the reaction between TAFIa and the developing clot. The use of TAFIa inhibitors as described above in terms of scope and utility, includes such TAFIa inhibitors which bind to TAFI.
The invention is further illustrated by the following, non-limiting examples.
Melting points were determined on a Gallenkamp melting point apparatus using glass capillary tubes and are uncorrected. Unless otherwise indicated all reactions were carried out under a nitrogen atmosphere, using commercially available anhydrous solvents. xe2x80x980.88 Ammoniaxe2x80x99 refers to commercially-available aqueous ammonia solution of about 0.88 specific gravity. Thin-layer chromatography was performed on glass-backed pre-coated Merck silica gel (60 F254) plates, and silica gel column chromatography was carried out using 40-63 xcexcm silica gel (Merck silica gel 60). Ion exchange chromatography was performed using with the specified ion exchange resin which had been pre-washed with deionised water. Proton NMR spectra were measured on a Varian Inova 300, Varian Inova 400, or Varian Mercury 400 spectrometer in the solvents specified. In the NMR spectra, only non-exchangeable protons which appeared distinct from the solvent peaks are reported. Low resolution mass spectra were recorded on either a Fisons Trio 1000, using thermospray positive ionisation, or a Finnigan Navigator, using electrospray positive or negative ionisation. High resolution mass spectra were recorded on a Bruker Apex II FT-MS using electrospray positive ionisation. Combustion analyses were conducted by Exeter Analytical UK. Ltd., Uxbridge, Middlesex. Optical rotations were determined at 25xc2x0 C. using a Perkin Elmer 341 polarimeter using the solvents and concentrations specified. Example compounds designated as (+) or (xe2x88x92) optical isomers are assigned based on the sign of optical rotation when determined in a suitable solvent.
Arbocel(trademark) Filtration agent, from J. Rettenmaier and Sohne, Germany
Amberlyst(copyright) Ion exchange resin, available from Aldrich Chemical Company
15
atm Pressure in atmospheres (1 atm=760 Torr=101.3 kPa)
Biotage(trademark) Chromatography performed using Flash 75 silica gel cartridge, from Biotage, UK
BOC tert-Butyloxycarbonyl group
br Broad
c Concentration used for optical rotation measurements in g per 100 ml (1 mg/ml is c 0.10)
cat Catalytic
d Doublet
dd Doublet of doublets
Degussa(copyright) 10 wt % palladium on activated carbon, Degussa type E101 available from
101 Aldrich Chemical Company
Dowex(copyright) Ion exchange resin, from Aldrich Chemical Company
ee Enantiomeric excess
HRMS High Resolution Mass Spectrocopy (electrospray ionisation positive scan)
Hyflo(trademark) Hyflo supercel(copyright), from Aldrich Chemical Company
liq liquid
LRMS Low Resolution Mass Spectroscopy (electrospray or thermospray ionisation positive scan)
LRMS (ESxe2x88x92) Low Resolution Mass Spectroscopy (electrospray ionisation negative scan)
m Multiplet
m/z Mass spectrum peak
MCI(trademark) gel High porous polymer, CHP20P 75-150 xcexcm, from Mitsubishi Chemical Corporation
psi Pounds per square inch (1 psi=6.9 kPa)
q Quartet
Rf Retention factor on TLC
s Singlet
Sep-Pak(copyright) Reverse phase C18 silica gel cartridge, Waters Corporation
t Triplet
TLC Thin Layer Chromatography
xcex4 Chemical shift